Objective: To establish a mouse model of severe pneumonia induced by sequential H1N1 influenza virus infection following Staphylococcus aureus (Fuxie) concealed pre-colonization in accordance with the traditional Chinese medicine (TCM) theory of “Fuxie,” and to preliminarily explore the pathogenic mechanism of Fuxie in the secondary severe disease model of H1N1 influenza infection. Methods: Balb/c mice were nasally colonized with S. aureus and subsequently infected with H1N1 influenza virus on days 30, 45, and 60 after colonization. Seven days post-infection, mice were euthanized by cervical dislocation for sample collection. Lung, spleen, and thymus indices were measured to evaluate organ injury. Lung histopathological changes were assessed by H E staining. Viral load and the expression levels of inflammation-related cytokines in lung tissues were detected by RT-qPCR, and alveolar macrophage subtypes were analyzed by flow cytometry. Results: Mice exhibited good general condition and steady weight gain following S. aureus concealed pre-colonization. After sequential H1N1 infection, both the influenza and S. aureus+influenza groups showed significant body weight loss (P<0.001), with the decrease being more pronounced in the S. aureus+influenza group. The lung index was significantly elevated in both infected groups (P<0.001). Histopathological examination revealed thickened alveolar walls and structural destruction in both groups, with more severe lesions in the S. aureus+influenza group. As the duration of S. aureus colonization increased, the differences in body weight loss and pathological damage between the two infected groups gradually diminished. RT-qPCR results showed that viral load and expression of inflammatory cytokine genes in lung tissues were markedly increased in both groups (P<0.001). Flow cytometric analysis demonstrated that after 30 days of S. aureus concealed pre-colonization, the proportion of M2-type alveolar macrophages significantly increased compared with the normal group (P<0.05). The proportions of M1-type macrophages were significantly elevated in both the influenza and S. aureus+influenza groups (P<0.001), while M2-type macrophages were also significantly increased in the S. aureus+influenza group (P<0.01). At 45 and 60 days of pre-colonization, no significant differences in alveolar macrophage polarization were observed among the groups. Conclusion: S. aureus concealed pre-colonization exacerbates host injury following secondary H1N1 influenza virus infection, but its impact diminishes with prolonged colonization time. The study establishes a mouse model of severe pneumonia consistent with the TCM theory of “Fuxie” using 30-day S. aureus concealed pre-colonization followed by H1N1 infection. Preliminary mechanistic findings suggest that S. aureus pre-colonization promotes M2 polarization of alveolar macrophages, suppresses host immune responses, and thereby contributes to severe pulmonary pathological damage during subsequent H1N1 influenza infection.